PROFILE

Profile of Charles L. Sawyers

harles Sawyers is a rock star in his Ras, a handful of research teams across own right. Last year, Sawyers, the country were hot on the trail of other Cchair of the Human Oncology oncogenes. Witte focused on the Phila- and Pathogenesis Program at delphia Chromosome, a genetic aberra- Memorial Sloan–Kettering Cancer Center tion that juxtaposes two genes, dubbed and a member of the National Academy BCR and ABL, when human chromo- of Sciences, posed with singer Debbie somes 9 and 22 swap segments, producing Harry of the rock band Blondie to pro- a hybrid enzyme in blood cells that jams mote cancer research in a campaign the cells’ growth restraints and leads to sponsored by the Geoffrey Beene Cancer CML. Patients with CML have a pro- Research Center. The unlikely assemblage fusion of frenetically dividing white blood of rock star and researcher shined the cells. Left unchecked, the disease can kill spotlight on pioneering efforts in trans- within 3 years of diagnosis. “This was an lational cancer research. Few physicians example of a cancer where the genetic deserve that spotlight more than Sawyers, abnormality was clear. That’s what at- who co-discovered the targeted cancer tracted me to Owen’s lab,” says Sawyers, drug, Gleevec, forging a path to cancer who joined the laboratory as a post- treatment that has now become increas- doctoral fellow in 1989. That move was ingly common. merely the opening act to a career punc- Born to physicians who served as a tuated by startling revelations, fruitful source of inspiration, Sawyers grew up in partnerships, life-saving discoveries, and a Nashville, Tennessee household where even heart-wrenching disappointments. medicine was the order of the day. A After 4 years of fundamental research standout in school, Sawyers excelled in on the biology of CML, Sawyers accepted science and mathematics. However, he an assistant professorship at UCLA’s headed toward college without the con- Charles L. Sawyers. Department of Medicine in 1993. Thanks, viction that his professional path was pre- in part, to a 1995 physician-scientist destined. “Although I was heavily exposed award from the National Cancer Institute, to medicine through my parents, my un- biology, which he realized would forge the Sawyers continued to study how BCR- cles, and my grandfather—all physicians, future of medicine. “My cousin pointed ABL signaling sent blood cells cascading I never felt like I was part of a lineage,” out mentors at UCSF with the patience toward cancer. Meanwhile, researchers he says. So, when it came time to choose to take on a smart kid with no elbow elsewhere were on the hunt for drugs to a field of study at college, Sawyers decided grease,” Sawyers says. One of those treat CML. Among them were two re- that the humanities could help widen mentors, infectious disease biologist Joel searchers whose names are now immor- his worldview. He majored in history at Ernst, now a professor of medicine at talized in the annals of cancer research: Princeton University, focusing on the his- New York University’s Langone Medical Oregon Health and Science University tory of science. At Princeton, Sawyers’ Center, became Sawyers’ partner in a molecular biologist Brian Druker and interest in the scientific method was 6-month-long stint performing molecular Ciba–Geigy (now Novartis) biochemist sparked by the writings of legendary sci- cloning experiments. To continue the Nicholas Lydon. Druker and Lydon hit ence historian Thomas Kuhn, whose apprenticeship, Sawyers decided to look upon a strategy to achieve what cancer storied opus, The Structure of Scientific for a postdoctoral position in molecular researchers had long sought: attacking Revolutions, has inspired generations of biology. During the early 1980s, California cancer cells while sparing normal cells. researchers pursuing science. was a hotbed of discoveries in biology, Using a tack that transformed cancer Sawyers’ scientifictemperamenttook and, in some ways, its epicenter was San treatment, the duo sought to disrupt the shape when, in 1981, he enrolled in the Francisco, then home to researchers like signaling pathways driven by BCR-ABL Johns Hopkins School of Medicine. There, Harold Varmus and Michael Bishop, who with a drug that could thwart the mutant Sawyers attended lectures in molecular bi- went on to unearth Nobel Prize-winning enzyme’s ability to spur cancer; normal ology with the eagerness of a budding findings in molecular oncology. cells, which lack the mutant enzyme, they physician intrigued by basic science. “When The laboratory Sawyers chose was reasoned, would be left unharmed. Logi- I learned that the clinical presentation of headed by University of California, Los cally appealing, the idea was not without some diseases could be narrowed down to Angeles (UCLA) molecular biologist its shortcomings; skeptics denounced single-nucleotide mutations, I was awe- Owen Witte, who discovered a leukemia- the attempt as misguided mostly because struck,” he says. Awe gave way to passion as causing protein produced by the fusion they believed other genetic flaws might Sawyers pored over volumes of basic bi- of a viral gene with a mouse gene; the also drive CML. Further, the skeptics ology literature, soon surpassing peers who human version of the protein is now well- decried, a drug that disrupted BCR-ABL had undergraduate degrees in science. To- known for its central role in triggering might harm any of the other dozens of ward the end of medical school, his cousin, a rare form of blood cancer called chronic similar life-sustaining cellular enzymes. a physician, recommended Sawyers move myeloid leukemia (CML) in people. “I However, the duo was not to be dis- across the country to complete his medical had taken care of patients with CML suaded. In 1996, they reported that a drug residency at the University of California during my medical studies, so the possi- called imatinib, now marketed as in San Francisco (USCF). bility of performing research on CML captivated me,” Sawyers says. In the wake California Calling of Massachusetts Institute of Technology ’ This is a Profile of a recently elected member of the Na- Sawyers arrived in California determined molecular biologist Robert Weinberg s tional Academy of Sciences to accompany the member’s to gain laboratory experience in molecular discovery of the first human oncogene, Inaugural Article on page 16759 in issue 39 of volume 107.

www.pnas.org/cgi/doi/10.1073/pnas.1107215108 PNAS | June 21, 2011 | vol. 108 | no. 25 | 10033–10035 Downloaded by guest on October 1, 2021 Gleevec, killed an experimental cancer enzyme to turn on pathways that kept the Freedom-to-Explore award from Bristol– cell line that needed BCR-ABL to grow cells in overdrive (2). Before long, Saw- Myers Squibb that allowed Sawyers to in laboratory dishes, although largely yer’s trainee Neil Shah had found more pursue risky high-stakes research. “Also, sparing other cancer cells that depended than a dozen such resistance-conferring I wanted to work on a disease that was on a different enzyme for their growth. mutations in the enzyme, making it near fairly common in the population, unlike The finding held when tested on normal impossible to design drugs to override CML, which is relatively rare,” Sawyers and cancer cells removed from patients, each mutation (3). However, through says of prostate cancer, which kills more showing that cancer cells could be suc- a fortunate turn of fate, Sawyers stumbled than 25,000 men each year in the United cessfully singled out for destruction. The upon a 2002 report in Science from Uni- States alone. Because androgens, or male discovery marked the dawn of a new versity of California, Berkeley structural sex hormones, fuel the growth of cells in era in cancer treatment: molecularly biologist John Kuriyan that described in the prostate gland, missteps in signaling targeted cancer therapy. illuminating detail the crystal structure of could lead to runaway cell division. The the ABL enzyme attached to Gleevec (4). standard approach to keep the cancer Hitting Cancer Where It Hurts Whereas some mutations physically hin- in check involves treatment with anti- The era began in 1995 when Druker and dered Gleevec’s access to the enzyme, the androgen drugs. As with leukemia, some Lydon enlisted the help of Sawyers to plan structure revealed, others changed the patients’ prostate cells develop resistance a multicenter dose and safety clinical trial enzyme’s overall shape. The shape- to the drugs. of Gleevec in patients with CML who changing mutations kept the enzyme in a Using an approach that has now be- failed to respond to IFN therapy, then so-called “on” state that disfavored the come his stock-in-trade in cancer research, the standard treatment for the disease. binding of Gleevec but allowed the en- Sawyers sought to determine what drove For these patients, bone marrow trans- zyme to spur cancer in white blood cells. drug resistance in prostate cells. Drug- plantation, risky and often ineffective, To keep the rebellious cells in check, resistant prostate cells, it turned out, make was the only other recourse. “Brian and I then, Sawyers would need to design drugs unusually high levels of androgen recep- had worked together on cancer signaling, that target the enzyme’s “on” state. tors, which powered their overactive sig- so when he approached me with Gleevec, Thus conceived, the idea yielded dasa- naling, rendering the drugs ineffective and I agreed, and we went to Basel to map tinib, the second-generation blockbuster the cells cancerous (6, 7). To quell the out the trial’s details with Nick Lydon,” drug marketed as Sprycel, thanks to a groundswell of aberrant signals, Sawyers Sawyers says. The trio launched the trial partnership with Bristol–Myers Squibb needed a drug that would gum up the in 1998 with unusually accelerated ap- biochemist Francis Lee (5). In 2006, the receptors. By screening a collection of proval from the US Food and Drug Ad- FDA approved Sprycel, which blocks chemical compounds that could bind to ministration (FDA). both the “on” and “off” states of BCR- the receptors, Sawyers’ team, in partner- The results of the trial are now the stuff ABL for patients with CML who have ship with UCLA biochemist Michael of legend. Hailed as a miracle drug, developed resistance to Gleevec. Today, Jung, identified a compound that showed Gleevec wiped out cancer cells in 53 of 54 thousands of patients with CML are promise in shrinking drug-resistant pros- chronic-stage patients who got adequate treated with Gleevec or Sprycel world- tate tumors in mice. The compound, doses of the drug. The patients’ white wide, turning death sentences into man- dubbed MDV3100, became a poster child blood cell counts plummeted over the ageable chronic conditions. The success of the pharmaceutical company Medi- first few weeks of therapy, and the drug of Gleevec spawned an armamentarium vation, which is testing the drug in men slashed the number of bone marrow cells of smart drugs in the war against cancer with drug-resistant prostate cancer who bearing the Philadelphia Chromosome in and helped whittle down cancer mortality failed to respond to both hormone ther- a third of the patients. Patients in late rates. In October 2009, Sawyers told apy and chemotherapy. More than half stages of the disease who faced near- journalist Charlie Rose on national tele- of the 140 men treated with the drug certain death walked out of the clinic vision, “If you understand the wiring [of showed declining levels of the prostate weeks after treatment with the drug, en- cancer cells] well enough, you can iden- antigen, a marker for prostate cancer, during mild side effects. The trial’s out- tify... the Achilles heel in the tumor and in their blood, raising hopes of success in come generated a drumbeat of good go after it with one drug, or as we’re now larger trials (8). “The drug is now in an publicity for the drug, marking a mile- learning... with multiple drugs.” international 1,200-patient, phase 3 trial, stone in cancer treatment. In 2001, the which could lead to the drug’s approval,” researchers reported in the New England New Challenge, Old Tack Sawyers says. One of the inventors of Journal of Medicine that the inhibitor was Sawyers has brought that reasoning to the drug, Sawyers holds a substantial well tolerated and effective in patients bear in his approach to treat prostate financial stake in its success. in late stages of CML (1). However, the cancer, a disease that affects more than Of the patients receiving MDV3100, optimism was soon tempered by the pre- 180,000 men each year. In 2006, he moved Sawyers anticipates, no fewer than half are dictably inevitable: CML evolved a way to the Memorial Sloan–Kettering Cancer likely to develop “intrinsic resistance” to to countervail the drug. Despite continued Center in New York City to lead a team the drug, likely reflecting the genetic treatment with Gleevec, some patients of physicians and researchers trying to makeup of the patients’ tumors. Of the relapsed, their cancers growing unchecked. usher basic research advances to the rest who might potentially benefit from Sawyers and his graduate student bedside, an endeavor called “trans- the drug, some will relapse because of Mercedes Gorre sifted through the lational medicine.” At Sloan–Kettering, “acquired resistance,” reflecting the can- genomes of white blood cells from patients where he has since served as a professor cer’s ability to thwart the drug through with CML who had developed resistance of medicine, Sawyers revisited cancer shape-shifting mutations. “We’re trying to to Gleevec and found a solution to the drug resistance—this time in patients re- understand how both kinds of resistance mystery of drug resistance. “Something ceiving antiandrogen drugs for metastatic develop. It’s a theme that has played out was restoring the ability of BCR-ABL to prostate cancer. Sawyers says he was in the past,” Sawyers says. This time, signal in cancer cells,” Sawyers says. A drawn to prostate cancer largely because however, the challenges are more daunt- mutation in the catalytic domain of the of the molecular tools and research dol- ing. Whereas researchers can readily BCR-ABL enzyme blocked Gleevec from lars available to study the disease. Part of recover circulating cancer cells for ex- binding to the enzyme, allowing the those dollars came from a generous 2003 perimental analysis from leukemia

10034 | www.pnas.org/cgi/doi/10.1073/pnas.1107215108 Nair Downloaded by guest on October 1, 2021 patients, tumors pepper the prostate addiction,” a name that befits the onco- for many drug targets. “So, in some ways, gland, bones, and lymph nodes of patients genes’ stranglehold over the cancer cells drug development puts the cart before with metastatic prostate cancer. So, ob- (9). Passenger mutations, on the other the horse. There are so many frustrating taining enough tumor samples would hand, are largely bystanders in cancer. examples in the last 10 years where mo- mean subjecting patients to grueling in- Mounting evidence from researchers lecularly targeted drugs have been de- vasive procedures. “That’s partly why we working on a range of cancers suggests clared failures because of a lack of are relying on preclinical models to study that targeting the driver mutations might biomarkers to test the status of the drug resistance,” Sawyers says. Preliminary slow the progression of cancer, if not stop targets in patients receiving the drugs,” studies using RNAi, a technique that it cold. To chart the panoply of drivers Sawyers says. The hope, then, is that allows researchers to muffle or scotch the and passengers in certain kinds of cancer, mining the cancer genome might yield production of target proteins, hinted that researchers are trying to create an atlas of clinically relevant biomarkers to guide the inability of the drug to inactivate cancer genomes, thanks to multinational diagnosis and treatment. androgen receptors, not an alternative efforts like The Cancer Genome Atlas For his contributions to the discovery cancer-driving mechanism, likely explains project and the International Cancer of Gleevec and Sprycel, Sawyers shared the resistance. Genome Consortium. The task is a Her- with Druker and Lydon the 2009 Lasker– culean one that could potentially yield DeBakey Clinical Medical Research Road to Personalized Cancer mountains of data but few drug targets Award, a bellwether honor that has often Treatment that pharmaceutical companies will con- preceded the Nobel Prize. “I was both The genomic revolution of the past decade sider profitable pursuits. “We certainly stunned and ecstatic when I heard the is no doubt changing the terrain in cancer need to continue to annotate the drivers news,” Sawyers says. treatment from a tissue-centered ap- and passengers, but we already have However, awards pale in comparison proach to a patient-centered one. How- enough of them to chase,” Sawyers says. to the payoff that Sawyers says motivates ever, the change is happening through “Once the pharmaceutical companies his efforts: the satisfaction of giving pa- measured moves rather than seismic have picked suitable inhibitors for the tients a new lease on life through the shifts. To take the road to personalized drivers, the baton gets passed to the molecular understanding of a disease of cancer treatment, researchers must first clinical trial community,” he adds. seismic fickleness. He hopes to translate distinguish drivers from passengers. The Therein lie a problem and its solution: the understanding into informed diagnosis, so-called “driver mutations,” which abet To be useful, molecularly targeted drugs drug development, and treatment op- the often-inexorable march of the disease, are best given to patients whose tumors tions for patients. “I believe we have the such as the BCR-ABL gene fusion in are likely to respond to the drugs, high- technology to do that systematically, but CML, act as the cancer’s life-support lighting the need to categorize patients it takes young champions in the clinic system, keeping the cancer cells de- based on cancer biomarkers instead of to make it happen,” he adds. pendent on them for their survival. Saw- lumping them together for treatment. yers calls this phenomenon “oncogene However, there are no reliable biomarkers Prashant Nair, Science Writer

1. Druker BJ, et al. (2001) Activity of a specific inhibitor of blast crisis chronic myeloid leukemia. Cancer Cell 2: 7. Watson PA, et al. (2010) Constitutively active androgen the BCR-ABL tyrosine kinase in the blast crisis of 117–125. receptor splice variants expressed in castration-resistant chronic myeloid leukemia and acute lymphoblastic 4. Schindler T, et al. (2000) Structural mechanism for STI- prostate cancer require full-length androgen receptor. leukemia with the Philadelphia chromosome. NEnglJ 571 inhibition of abelson tyrosine kinase. Science 289: Proc Natl Acad Sci USA 107:16759–16765. Med 344:1038–1042. 1938–1942. 8. Scher HI, et al.; Prostate Cancer Foundation/Depart- 2. Gorre ME, et al. (2001) Clinical resistance to STI-571 5. Shah NP, et al. (2004) Overriding imatinib resistance ment of Defense Prostate Cancer Clinical Trials Con- cancer therapy caused by BCR-ABL gene mutation or with a novel ABL kinase inhibitor. Science 305:399– sortium (2010) Antitumor activity of MDV3100 in amplification. Science 293:876–880. 401. castration-resistant prostate cancer: A phase 1-2 study. 3. Shah NP, et al. (2002) Multiple BCR-ABL kinase domain 6. Chen CD, et al. (2004) Molecular determinants Lancet 375:1437–1446. mutations confer polyclonal resistance to the tyrosine of resistance to antiandrogen therapy. Nat Med 10: 9. Sawyers CL (2009) Shifting paradigms: The seeds of kinase inhibitor imatinib (STI571) in chronic phase and 33–39. oncogene addiction. Nat Med 15:1158–1161.

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